Human Immunodeficiency Virus Type 1 (HIV-1) is the etiologic agent of AIDS in Central Africa, Europe, the United States and most countries worldwide. Recently a second group of immunodeficiency-associated retroviruses, designated HIV-2 was discovered in West Africa. HIV-2 is related to HIV-1, but differs from the prototype AIDS virus in its geographic distribution, its protein structure and antigenicity, as well as its nucleotide sequence and genomic organization. Also, while HIV-1 infection in populations worldwide has been associated with immune suppression and AIDS, infection with HIV-2 has not uniformly been associated with disease. In this project we propose to define determinants of HIV-2 pathogenicity in order to evaluate whether this virus, or certain strains of it, differ from HIV-1 in a biologically important way. To achieve this we will take two basic approaches: (i) we will study the function and significance of particular genes and regulatory sequences which are unique for HIV-2 and are not present in HIV-1. (ii) we will characterize on a molecular level naturally-occurring variants of HIV-2, which differ in their pathogenic potential. Specifically, we will a) define in vitro biological differences of HIV-2 variants using transfection-derived viral strains; b) identify those genes and/or regulatory regions that render certain strains of HIV-2 less cytopathic; c) compare and contrast envelope properties of naturally-occurring HIV-2 variants with respect to syncytia forming and cell killing abilities; d) determine the transcriptional map of HIV-2; e) elucidate the function of the novel HIV-2 X gene; and, f) express this gene for the development of specific reagents and X-ray crystallography. We expect these studies to yield important and new information regarding HIV-2 biology and pathobiology. We will perform the proposed experiments in direct collaboration with Dr. Casey Morrow (Project #4) and Dr. Richard Compans (Project #3), but our results will also be of importance and value to all other investigators of this program project who study HIV replication and pathogenesis.